Role of cellular senescence in hepatic wound healing and carcinogenesis

Ramakrishna, Gayatri; Anwar, Tarique; Angara, Rajendra Kumar; Chatterjee, Nirupama; Kiran, Shashi; Singh, Sapna

doi:10.1016/j.ejcb.2012.08.002

Cited by 19 publications

(8 citation statements)

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“…Cellular senescence is a state of irreversible growth arrest and is induced by a wide variety of conditions, including telomere shortening (replicative senescence) and telomere-independent signals (stress-induced senescence) [29,30]. Previous reports have demonstrated that cigarette smoke induces airway epithelial cellular senescence [20,21] and senescent cells are readily detected in airway epithelia of patients with COPD [31].…”

Section: Resultsmentioning

confidence: 99%

Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

Dong

Wang

et al. 2013

PLoS ONE

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BackgroundAirway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma.ObjectivesTo examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo.MethodsCellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma.ResultsActivation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance.ConclusionTSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling.

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Section: Resultsmentioning

confidence: 99%

Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

Dong

Wang

et al. 2013

PLoS ONE

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“…The occurrence of senescent cells in ageing and the development of cirrhosis points to their role in underlying pathology [73,77]. Hepatocyte senescence is intricately linked to telomerase and telomere biology.…”

Section: Cellular Senescence: the Yin And Yang In Hcc Progressionmentioning

confidence: 99%

“…A senescent parenchymal or nonparenchymal cell in a premalignant or benign setting can have beneficial effects in terms of resolution of fibrosis or the clearing of prospective malignant cells, thereby working as an “anticancer bullet.” On the other hand, if parenchymal cells, which constitute the bulk of the liver, undergo senescence en masse, it will lead to compromised liver function and will be deleterious. Consequently, senescence appears to be a double-edged sword with opposing functions in the complex organ that is the liver [77]. …”

Section: Cellular Senescence: the Yin And Yang In Hcc Progressionmentioning

confidence: 99%

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna¹,

Rastogi²,

Trehanpati³

et al. 2013

Liver Cancer

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182

121

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Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the “inflammasome” (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

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“…In coherence with HCV-associated HCC progression, some relevant biological processes were discovered, such as "viral reproduction" (cluster I), "interspecies interaction between organisms" (cluster III and cluster IV), and "wound healing" (cluster V) [33]. …”

Section: Resultsmentioning

confidence: 99%

“…Seven genes in cluster V are involved in "negative regulation of apoptotic process", and their enhanced correlations in the advanced HCC samples likely indicate an ultimate breakdown of the apoptosis program. Other potentially relevant terms tagged to cluster V include "wound healing" and "MAPK cascade," which are functions frequently implicated in carcinogenesis or cancer metastasis [33,34]. Cluster IV, a group of protein interaction pairs with collapsed correlations in advanced HCC, is enriched with "interspecies interaction between organisms.…”

Section: Resultsmentioning

confidence: 99%

Dynamic protein interaction modules in human hepatocellular carcinoma progression

Chen

et al. 2013

BMC Syst Biol

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BackgroundGene expression profiles have been frequently integrated with the human protein interactome to uncover functional modules under specific conditions like disease state. Beyond traditional differential expression analysis, differential co-expression analysis has emerged as a robust approach to reveal condition-specific network modules, with successful applications in a few human disease studies. Hepatocellular carcinoma (HCC), which is often interrelated with the Hepatitis C virus, typically develops through multiple stages. A comprehensive investigation of HCC progression-specific differential co-expression modules may advance our understanding of HCC's pathophysiological mechanisms.ResultsCompared with differentially expressed genes, differentially co-expressed genes were found more likely enriched with Hepatitis C virus binding proteins and cancer-mutated genes, and they were clustered more densely in the human reference protein interaction network. These observations indicated that a differential co-expression approach could outperform the standard differential expression network analysis in searching for disease-related modules. We then proposed a differential co-expression network approach to uncover network modules involved in HCC development. Specifically, we discovered subnetworks that enriched differentially co-expressed gene pairs in each HCC transition stage, and further resolved modules with coherent co-expression change patterns over all HCC developmental stages. Our identified network modules were enriched with HCC-related genes and implicated in cancer-related biological functions. In particular, APC and YWHAZ were highlighted as two most remarkable genes in the network modules, and their dynamic interaction partnership was resolved in HCC development.ConclusionsWe demonstrated that integration of differential co-expression with the protein interactome could outperform the traditional differential expression approach in discovering network modules of human diseases. In our application of this approach to HCC's gene expression data, we successfully identified subnetworks with marked differential co-expression in individual HCC stage transitions and network modules with coherent co-expression change patterns over all HCC developmental stages. Our results shed light on subtle HCC mechanisms, including temporal activation and dismissal of pivotal functions and dynamic interaction partnerships of key genes.

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Role of cellular senescence in hepatic wound healing and carcinogenesis

Cited by 19 publications

References 91 publications

Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Dynamic protein interaction modules in human hepatocellular carcinoma progression

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